Vitamin B12, a well-known micronutrient celebrated for its pivotal role in nerve function, red blood cell production, and DNA synthesis, has now emerged as a key player in cellular reprogramming and tissue regeneration. Researchers led by Dr. Manuel Serrano at IRB Barcelona have made groundbreaking discoveries regarding the significant impact of vitamin B12 on cellular processes, shedding light on its therapeutic potential and broader implications for regenerative medicine.
Vitamin B12 – A Multifaceted Micronutrient
Vitamin B12, also known as cobalamin, stands as a crucial cobalt-containing micronutrient essential for human health. It is a product of synthesis by specific bacteria and archaea, regulated by bacterial riboswitches . While certain gut microbes can produce B12, its absorption relies on the presence of cubilin, a receptor expressed exclusively by ileal epithelial cells (iECs) . This exclusivity is noteworthy, as the ileum generally harbors low microbial abundancy and diversity .
In the human diet, particularly in animal products, B12 finds its primary natural source . Consequently, individuals adhering to vegetarian or vegan diets often exhibit lower serum B12 levels . The journey of B12 from food to tissues involves a complex interplay of various transport proteins and receptors. The process includes release in the upper gastrointestinal tract, binding to intrinsic factor (IF), and absorption by ileal epithelial cells through cubilin-mediated mechanisms .
Once in circulation, B12 binds to transcobalamin and is taken up by CD320-expressing cells . Inside the human body, B12 serves as a co-factor for two enzymes: cytosolic methionine synthase (MS) and mitochondrial methylmalonyl-CoA mutase (MCM). MS is pivotal in methionine biosynthesis, a process critical for DNA methylation [7,10]. VB12 deficiency impairs MS activity, leading to hyperhomocysteinemia and an increased risk of cardiovascular and neurological diseases [8,9]. The role of B12 in DNA methylation remains a subject of controversy, necessitating further investigation [11-15].
In the mitochondria, B12’s partnership with MCM is crucial for converting methylmalonyl-CoA to succinyl-CoA. This process not only contributes to the tricarboxylic acid (TCA) cycle but also impacts heme biosynthesis, essential for erythropoiesis and cellular respiration [16,17]. Pernicious anemia and hematological manifestations are linked to B12 deficiency, along with the accumulation of serum methylmalonic acid causing methylmalonic aciduria [18,19].
Recent studies suggest that B12 deficiency may disrupt mitochondrial homeostasis [22,23]. In humans, elevated methylmalonic acid levels have been associated with cardiovascular mortality, possibly due to mitochondrial dysfunction and oxidative stress . The intricate connection between B12 and mitochondrial regulation remains a subject of ongoing research.
In a recent study on mice, we demonstrated that VB12 deficiency influences mitochondrial gene expression and carnitine shuttle activity in ileal epithelial cells . This deficiency also impacts gut microbiota-associated fatty acids, influencing peroxisome proliferator-activated receptor (PPAR) signaling during intestinal infection. The compromised mitochondrial activity correlates with increased vulnerability to Salmonella infection in VB12-deficient mice. Furthermore, VB12 deficiency affects the production of propionate and butyrate in the distal gut, potentially inhibiting the expression of Salmonella virulence genes crucial for epithelial invasion.
Despite the significance of VB12 supplementation in regulating iECs and microbiota functions in mice, the direct causative relationship between VB12 and iEC–mitochondrial metabolism remains elusive. Sparse evidence exists on direct associations between VB12 and iEC function in humans. Utilizing a 3-dimensional microtissue model, we explored the impacts of VB12 on the transcriptomic, metabolomic, and epigenetic programming of human iECs in vitro.
Our findings suggest that VB12 not only facilitates fatty acid and mitochondrial metabolisms but also sustains DNA methylation programs essential for epithelial cell proliferation and function. This research underscores the intricate and multifaceted role of Vitamin B12 in human health, encouraging further exploration and understanding of its diverse functions.
Cellular Reprogramming and Vitamin B12: The focus of the research led by Dr. Serrano was on cellular reprogramming, a process mimicking early stages of tissue repair. Astonishingly, the team found that this process in mice consumes substantial amounts of vitamin B12. The depletion of vitamin B12 emerged as a limiting factor, causing delays and impairments in reprogramming. Intriguingly, the simple supplementation of vitamin B12 significantly enhanced the efficiency of the reprogramming process, revealing a previously unexplored dimension of the vitamin’s influence.
Therapeutic Potential in Ulcerative Colitis: To validate their findings, the researchers applied their discoveries to a model of ulcerative colitis, where intestinal cells undergoing repair exhibit a process similar to cellular reprogramming. The supplementation of vitamin B12 showed promising results, suggesting potential therapeutic applications for patients with intestinal bowel disease. Dr. Manuel Serrano emphasized, “Our research uncovers a critical role of vitamin B12 in cellular reprogramming and tissue repair. These findings hold promise for regenerative medicine, with the potential to benefit patients through improved nutrition.”
Metabolic Insights into Cellular Reprogramming: Delving into the metabolic requirements of cellular reprogramming, researchers discovered that vitamin B12 plays a crucial role in a specific branch of metabolism involved in methylation reactions. The DNA of cells initiating reprogramming requires high levels of this reaction and, consequently, vitamin B12. Insufficiency during reprogramming led to significant epigenetic changes, resulting in errors in the function of multiple genes. Supplementation with vitamin B12 corrected these imbalances, enhancing gene function fidelity and overall reprogramming efficiency.
Anti-Inflammatory Action of Vitamin B12: In a separate study, Dr. Serrano’s group, in collaboration with other research teams, linked higher levels of vitamin B12 in blood to lower levels of inflammatory markers (IL-6 and CRP). This anti-inflammatory action observed in both humans and aged mice suggests that vitamin B12 may contribute to reducing inflammation in the body, providing valuable insights into its potential health benefits beyond its well-established roles.
Collaborative Research Effort: This research project was a collaborative effort involving various institutions and researchers, including Dr. Guido Kroemer in France, Dr. Oscar Yanes in Spain, IRB Barcelona’s Bioinformatics and Biostatistics Core Facility, and the Histopathology Core Facility. The comprehensive approach allowed for a multifaceted exploration of vitamin B12’s role in cellular reprogramming and tissue regeneration.
Conclusion: Dr. Manuel Serrano’s pioneering research has uncovered a previously unknown role of vitamin B12 in cellular reprogramming and tissue repair. The findings not only deepen our understanding of the metabolic intricacies involved in these processes but also open new avenues for regenerative medicine and potential therapeutic interventions, particularly in conditions like ulcerative colitis. As we continue to unveil the diverse roles of micronutrients, the significance of vitamin B12 extends beyond its conventional associations, promising a healthier future through improved nutrition and targeted interventions.
reference link : https://www.nature.com/articles/s42255-023-00917-5